Dissertation Defense: Phillip Gross
Candidate: Phillip Gross
Advisor: Jeffrey Huang, Ph.D.
Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Multiple Sclerosis (MS) is a chronic demyelinating disease where increased age is associated with inefficient remyelination, resulting in degeneration of axons and worsening of symptoms. However, the impact of senescent cells (SC), whose accumulation is often associated with aging, remains unexplored in the demyelinated CNS. Here, we observe an increase in SCs following demyelination and that SC depletion stimulates increased remyelination. Using a murine reporter line for p161NK4a, we found an increase in senescence early post-lesion, with expression decreasing throughout remyelination. These markers predominantly colocalized with microglia. Additionally, MERFISH analysis and immunofluorescence showed increased, prolonged SCs with age, correlating with reduced remyelination. SC depletion resulted in increased remyelination, and senescence associated secretory phenotype reduction. RNA-sequencing and multiplexing identified multiple prospective targets for this improvement, including Eotaxin-1/CCL11, which when inhibited, partially replicated the beneficial effects of SC depletion. These results suggest that targeting of cellular senescence might promote remyelination in MS.